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GGNBP2 acts as a tumor suppressor by inhibiting estrogen receptor α activity in breast cancer cells

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Abstract

Gametogenetin-binding protein 2 (GGNBP2) is encoded in human chromosome 17q12-q23, a region known as a breast and ovarian cancer susceptibility locus. GGNBP2, also referred to ZFP403, has a single C2H2 zinc finger and a consensus LxxLL nuclear receptor-binding motif. Here, we demonstrate that GGNBP2 expression is reduced in primary human breast tumors and in breast cancer cell lines, including T47D, MCF-7, LCC9, LY2, and MDA-MB-231 compared with normal, immortalized estrogen receptor α (ERα) negative MCF-10A and MCF10F breast epithelial cells. Overexpression of GGNBP2 inhibits the proliferation of T47D and MCF-7 ERα positive breast cancer cells without affecting MCF-10A and MCF10F. Stable GGNBP2 overexpression in T47D cells inhibits 17β-estradiol (E2)-stimulated proliferation as well as migration, invasion, anchorage-independent growth in vitro, and xenograft tumor growth in mice. We further demonstrate that GGNBP2 protein physically interacts with ERα, inhibits E2-induced activation of estrogen response element-driven reporter activity, and attenuates ER target gene expression in T47D cells. In summary, our in vitro and in vivo findings suggest that GGNBP2 is a novel breast cancer tumor suppressor functioning as a nuclear receptor corepressor to inhibit ERα activity and tumorigenesis.

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Acknowledgments

We thank Drs. Ray Wu, John Lydon, and Bert W. O’Malley for kindly providing human estrogen receptor expression vectors, ERE-luciferase plasmids, mammary RNA from normal and Wnt1 transgenic mice. We also thank Dr. Robert Clarke for graciously providing LCC9 and LY2 cells.

Funding

This work was supported in part by Grants R01-HD057501 (ZM Lei), 5P20RR017702-10, and 8P20 GM103453-10, project I (ZJ Lan) from the National Institutes of Health, USA, University of Louisville School of Medicine (CM Klinge), and 12ZCDZSY15700 (J Zhang) from Tianjin municipal Major Scientific and Technological Special Project for Significant Anticancer Development and Chinese National Natural Sciences Foundation 81402480 (YH Hu), China.

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    Authors and Affiliations

    1. Division of Life Sciences, Center for Nutrigenomics & Applied Animal Nutrition, Alltech Inc., Nicholasville, KY, 40356, USA

      Zi-Jian Lan

    2. The 3rd Department of Breast Cancer, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute & Hospital, 500 South Preston Street, Hu-Xi District, 300060, Tianjin, People’s Republic of China

      YunHui Hu, Sheng Zhang & Jin Zhang

    3. Department of OB/GYN & Women’s Health, University of Louisville Health Sciences Center, 500 South Preston Street, Louisville, KY, 40292, USA

      Xian Li & Zhenmin Lei

    4. Birth Defects Center, Department of Molecular, Cellular and Craniofacial Biology, University of Louisville Health Sciences Center, Louisville, KY, 40292, USA

      Huaxin Zhou & Jixiang Ding

    5. Department of Biochemistry & Molecular Genetics, University of Louisville Health Sciences Center, Louisville, KY, 40292, USA

      Carolyn M. Klinge & Brandie N. Radde

    6. Department of Pediatrics, The University of Texas at Austin Dell Medical School, Austin, TX, 78712, USA

      Austin J. Cooney

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    1. Zi-Jian Lan
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    Zi-Jian Lan and YunHui Hu have contributed equally to this work.

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    Lan, ZJ., Hu, Y., Zhang, S. et al. GGNBP2 acts as a tumor suppressor by inhibiting estrogen receptor α activity in breast cancer cells. Breast Cancer Res Treat 158, 263–276 (2016). https://doi.org/10.1007/s10549-016-3880-2

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